Inhibitors of cellular metabolic processes

Abstract

The present disclosure provides MAT2A inhibitor compounds that are useful as therapeutic agents for treating malignancies, and wherein the compounds conform to general formula (IA): wherein R A , R B , R C , R D , and R E are defined herein.

We claim: 
     
       1. A compound according to formula IA or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein:
 R A  is NR 1 R 2 ; 
 R B  is H, C 2 -C 6 -alkenyl, or C 1 -C 6 -alkyl, wherein R B  is optionally substituted by one or more of R 1 ; 
 R C  and R E  are C 6 -C 14 -aryl; 
 R D  is C 3 -C 14 -carbocycle or C 6 -C 14 -aryl;
 wherein R C , R D , and R E  are optionally substituted with one or more of R 1 , —OR 1 , halo, —NR 1 R 2 , —(C 1 -C 6 -alkyl)-NR 1 R 2 , —C(O)OR 1 , —C(O)NR 1 R 2 , —NO 2 , —CN, or oxo; and 
 
 R 1  and R 2  are, independently, H, D ( 2 H), —CN, —OH, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, NH 2 , —S(O) 0-2 —(C 1 -C 6 -alkyl), —S(O) 0-2 —(C 6 -C 14 -aryl), —C(O)(C 1 -C 6 -alkyl), —C(O)(C 3 -C 14 -carbocyclo), —C 3 -C 14 -carbocycle, C 6 -C 14 -aryl, 3- to 14-membered heterocycle (wherein 1 to 4 heterocycle ring members are heteroatoms that are N, O, or S) or heterocyclo(C 1 -C 6 -alkyl)- (wherein 1 to 4 heterocycle ring members are heteroatoms that are N, O, or S);
 wherein each alkyl, alkoxy, alkenyl, alkynyl, aryl, carbocycle, and heterocycle moiety of R 1  and R 2  is optionally substituted with one or more of hydroxy, halo, —NH 2 , —NHC(O)(OC 1 -C 6 -alkyl), —NO 2 , —CN, oxo, —C(O)OH, —C(O)O(C 1 -C 6 -alkyl), —C 1 -C 6 -alkyl(C 1 -C 6 -alkoxy), —C(O)NH 2 , C 1 -C 6 -alkyl, —C(O)C 1 -C 6 -alkyl, —OC 1 -C 6 -alkyl, —Si(C 1 -C 6 -alkyl) 3 , C 6 -C 14 -aryl, —(C 1 -C 6 -alkyl)(C 6 -C 14 -aryl), 3- to 14-membered heterocycle or heterocyclo(C 1 -C 6 -alkyl)- (wherein 1 to 4 heterocycle ring members are heteroatoms that are N, O, or S), or —O(C 6 -C 14 -aryl), 
 wherein each alkyl, aryl, and heterocyclo in R 1  and R 2  is optionally substituted with one or more of hydroxy, —OC 1 -C 6 -alkyl, halo, —NH 2 , —(C 1 -C 6 -alkyl)NH 2 , —C(O)OH, CN, or oxo. 
 
 
       
     
     
       2. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R D  and R E  are C 6 -C 10 -aryl. 
     
     
       3. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R D  is cyclopentyl, cyclopentenyl, cyclohexyl, or cyclohexenyl. 
     
     
       4. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R D  is cyclohexyl or cyclohexenyl and R E  is phenyl. 
     
     
       5. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is H. 
     
     
       6. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R D  is optionally substituted with one or more of hydroxy, halogen, —NH 2 , —C(O)OH, —CN, oxo, alkyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, or (C 1 -C 6 -alkyl)N(H)—;
 wherein the C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, and (C 1 -C 6 -alkyl)N(H)— are optionally substituted with one or more of hydroxy, halogen, —NH 2 , —C(O)OH, —CN, or oxo. 
 
     
     
       7. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R D  is cyclohex-1-en-1-yl. 
     
     
       8. The compound of to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R E  is phenyl. 
     
     
       9. The compound of  claim 8 , or a pharmaceutically acceptable salt thereof, wherein R D  is cyclohex-1-en-1-yl. 
     
     
       10. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R C  is 4-hydroxyphenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-trifluoromethoxyphenyl, 4-hydroxy-2-methylphenyl, 4-hydroxy-2-methoxyphenyl, 3,4-dihydroxyphenyl, 4-(2,2,2-trifluoroethoxy)phenyl, 4-(2-(dimethylamino)ethoxy)phenyl, 3-fluoro-4-hydroxyphenyl, 3-fluoro-4-methoxyphenyl, 2-chloro-4-hydroxyphenyl, 2-fluoro-4-methoxyphenyl, 3-amino-4-hydroxyphenyl, 3-amino-4-fluorophenyl, 3-(N,N-dimethylaminoethoxy)-4-hydroxyphenyl, 3-chloro-2-hydroxyphenyl, 3-hydroxyethoxy-4-hydroxyphenyl, or 
       
         
           
           
               
               
           
         
       
     
     
       11. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R C  is 4-methoxyphenyl. 
     
     
       12. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is a 3- to 14-membered heterocycle optionally substituted with one or more substituents of hydroxy, halogen, —NH 2 , —NO 2 , —C(O)OH, —C(O)OC 1 -C 6 -alkyl, (C 1 -C 6 -alkyl)N(H)C(O)—, —CN, oxo, C 1 -C 6 -alkyl, —C(O)H, C 1 -C 6 -alkoxy, or (C 1 -C 6 -alkyl)N(H)—,
 wherein the C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, (C 1 -C 6 -alkyl)N(H)—, C(O)OC 1 -C 6 -alkyl, and (C 1 -C 6 -alkyl)N(H)C(O)— are optionally substituted with one or more of hydroxy, halogen, —NH 2 , (C 1 -C 6 -alkyl)N(H)—, —C(O)H, —CN, or oxo. 
 
     
     
       13. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is pyridin-2-yl, pyrazin-2-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, 1,3,5-triazin-2-yl, or 1,2,4-triazin-3-yl, each of which is optionally substituted with one or more of F, C 1 , CN, OH, —NO 2 , —NH 2 , —NHMe, —C(O)NH 2 , or methoxy. 
     
     
       14. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is: 
       
         
           
           
               
               
           
         
       
     
     
       15. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is: 
       
         
           
           
               
               
           
         
       
     
     
       16. A method for inhibiting the synthesis of S-adenosyl methionine (SAM) from methionine and ATP by MAT2A in a cell, comprising introducing into the cell an effective amount of a compound, or a pharmaceutically acceptable salt thereof, of  claim 1 . 
     
     
       17. A method for treating a cancer in a subject suffering therefrom, wherein the cancer is MTAP null, the method comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, of  claim 1 . 
     
     
       18. The method of  claim 17 , wherein the cancer is neuroblastoma, rectum carcinoma, colon carcinoma, familial adenomatous polyposis carcinoma and hereditary non-polyposis colorectal cancer, esophageal carcinoma, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tongue carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, renal carcinoma, kidney parenchyma carcinoma, ovarian carcinoma, cervix carcinoma, uterine corpus carcinoma, endometrium carcinoma, chorion carcinoma, pancreatic carcinoma, prostate carcinoma, testis carcinoma, breast carcinoma, urinary carcinoma, melanoma, brain tumor acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CIVIL), adult T-cell leukemia, lymphoma, hepatocellular carcinoma, gall bladder carcinoma, bronchial carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma, choroidea melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma, or plasmocytoma. 
     
     
       19. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
       20. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       21. The compound of  claim 1  that is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       22. The compound of  claim 1  that is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       23. The compound of  claim 1  that is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       24. The method of  claim 17 , wherein the brain tumor is as glioblastoma, astrocytoma, meningioma, medulloblastoma, or peripheral neuroectodermal tumor. 
     
     
       25. The method of  claim 17 , wherein the lymphoma is Hodgkin lymphoma, non-Hodgkin lymphoma, or Burkitt lymphoma.